Adamantoate esters of testosterone



United States Patent 3,261,852 ADAMANTOATE ESTERS 0F TESTOSTERONE Richard T. Rapala, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Filed July 6, 1964, Ser. No. 380,627 4 Claims. (Cl. 260397.4)

This invention relates to certain novel esters of testosterone and related compounds.

The compounds provided :by this invention are testosterone 17fi-(1-ada-mantoate), 19-nortestosterone 175-(1- ada man-toate), and 4-chlorotestosterone l7r3-(1-adamantoate). They are esters of testostrene, l9nortestosterone, and 4-chlorotestosterone with adamantane-lcarboxylic acid, which acid can be represented by the following formula:

Also included within the scope of this invention as equivalent to the adamantane-l-canboxylic acid esters are the esters of the lower alkyl substituted adamantane4-carboxylic acids such as 3-methyl and 3,5-dimethyladamantane-l-carboxylic acid.

The compounds of this invention have a surprisingly high rnyotrophic/androgenic ratio when compared with the parent alcohol from which they are derived .and with other marketed nortestosterone and testosterone ester anabolic agents. This favorable ratio manifests itself in animals as an enhanced anabolic activity with a minimum of androgenic activity as compared with the parent compound. In animals, the myotrophic response of our novel esters is considerably delayed and/ or prolonged, compared with the myotropic response to aliphatic esters of the same alcohols. In addition, the compounds of this invention are surprisingly void of antiestrogenic activity, whereas the parent alcohols are all three potent antiestrogenic agents.

The compounds of this invention are white, crystalline, high-melting solids, soluble in most organic solvents. They are prepared by standard esterification procedures using as the acylating agent either adamantanecar-boxylic acid chloride or adamantanecarboxylic acid anhydride or the mixed anhydride of adamantanecarboxylic acid and trifiuoroacetic acid, usually in the presence of a small quantity of pyridine or other tertiary amine as a catalyst.

The following examples will more fully illustrate the preparation of the compounds of this invention.

EXAMPLEI 4-chlor0test0ster0ne 1 7 8- (1 -adamant0ate) A solution was prepared containing 450 mg. of 4- 3,261,852 Patented July 19, 1966 chlorotestosterone and 50 ml. of anhydrous benzene. A second solution containing 332 mg. of adamantanecarboxylic acid chloride in 5 ml. of anhydrous benzene was added, followed by 0.2 ml. of pyridine. The resulting reaction mixture was heated to refluxing tempera'ture for about two hours. A mixture of water and ether Was then added. The organic layer was separated, and was washed with a saturated sodium carbonate solution, then with Water. The organic layer was again separated and was dried and the volatile constitutents were removed therefrom by evaporation in vacuo. The resulting residue, comprising 4-chlorotestosterone 17fi-(1- adamantoate), was crystallized by dissolution in ml. of ether, reducing the ether volume to about 15 ml. by boiling, and then cooling the resulting concentrate. The crystals thus obtained were recrystallized from acetone to yield 4-chlorotestosterone l7/3-(1-adamant0ate) melting at about 304306 C. with decomposition. Analysis. Calc.: C, 74.27; H, 8.51. Found: C, 74.31; H, 8.59.

EXAMPLE II Preparation of 19-n0rtestoster0ne 1 7 ,8- (1 -adamant0atc) 19-nortestosterone 17fi-(1-adamantoate) was prepared by the procedure of Example I by substituting 384 mg. of 19-nortestosterone for the steroid of that example. 19-nortestosterone l7fl-(l-adamantoate) thus obtained melted at about 204-206 C. Analysis.-Ca1c.: C, 79.77; H, 9.23. Found: C, 79.69; H, 9.30.

EXAMPLE HI Testosterone 1 7 3-(1-adamant0ate) Testosterone 17 8-(1-adamantoate) was prepared by the procedure of Example I except that 400 mg. of testosterone were su-bstitu-ted for the steroid of that example. Testosterone 17/3-(l-adamantoate) thus prepared melted at about 217220 C. Analysis-Calc.: C, 79.95; H, 9.39. Found: C, 79.73; H, 9.44.

I claim:

1. A compound selected from the group consisting of 4-chlorotestosterone 17B-(1-adamantoate), 19-nortestosterone 17/3-(1-adamantoate) and testosterone 17/8-(1- adamantoate) 2. 4-chlor-otestosterone 17/3-(1-adamantoate).

3. 19-nortestoster0ne 17/i(1-adamantoate) 4. Testosterone 17fi-(1-adamantoate).

References Cited by the Examiner FOREIGN PATENTS 826,790 10/1960 Great Britain.

OTHER REFERENCES Dorfman et al.: Androgens, pp. 116 128 (1960), John Wiley & Sons, New York.

Loewenthal: Tetrahedron, vol. 6, pp. 269-303 (1959), pages 299-303.

LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4-CHLOROSTESTOSTERONE 17B-(1-ADAMANTOATE9, 19-NORTESTOSTERONR 17B-(1-ADAMANTOATE) AND TESTOSTERONE 17B-(1ADAMANTOATE). 